Retroperitoneal fibrosis

* We report a rare autopsy case of secondary gastrointestinal amyloid A (AA) amyloidosis associated with idiopathic retroperitoneal fibrosis (IRF) in a 67-year-old woman. Masses were identified around the aorta and inferior vena cava in her abdomen. Histologically, plasma cell infiltration was observed within fibrotic areas. Because no specific cause for the inflammatory mass was apparent, we diagnosed it as IRF. Steroid therapy, which usually reduces IRF masses, proved ineffective, and malabsorption syndrome developed 4 years later. On autopsy, amyloid protein was present systemically in the vascular walls of several organs, and deposition was highest in the gastrointestinal mucosa. Amyloid protein was identified as AA type, strongly suggesting that the amyloidosis was secondarily induced by IRF. To our knowledge, only 2 other cases of IRF-associated amyloidosis have been reported. Two of the 3 patients of these cases were women who showed resistance to steroid therapy.

Idiopathic retroperitoneal fibrosis (IRF) is a rare disease and was established by Ormond as a clinical entity in 1948.(1) The disease forms a chronic inflammatory mass in the retroperitoneum and typically occurs in middle age, with a male-female ratio of about 3:1.(1) The mass frequently envelops the aorta, vena cava, ureter, or nerves. Hypertension, lower-extremity edema, urinary symptoms, and pain are therefore common symptoms. Typical histologic findings for IRF are plasma cell infiltration with fibrosis.2 Although chronic immune reactions may play an important role in the pathogenesis of IRF, the etiology is poorly understood. Surgical resection of the mass is effective for the temporary attenuation of symptoms, but the mass and symptoms gradually recur. Steroid therapy usually shows good efficacy in reducing the symptoms and size of the mass unless the fibrosis is well advanced.1

Amyloidosis is a functional disorder marked by unusual depositions of amyloid protein in various organs. Amyloid A (AA) amyloidosis is a secondary disorder induced by chronic infection or inflammation, such as osteomyelitis tuberculosis, rheumatoid arthritis, or granulomatous ileitis.3 However, only a small percentage of patients with certain chronic inflammatory diseases develop amyloidosis. Although various possible factors have been postulated,4 the exact etiologic mechanisms remain unknown. For diagnosis, amyloid deposits are stained with Congo red and emit green-yellow light upon polarization. They can also be stained with Thioflavan T or S. In addition, potassium permanganate Congo red staining and immunohistochemical staining for AA components can identify AA proteins. The primary treatment of AA amyloidosis involves the reduction of inflammatory activity from the primary disease.3

We report a rare autopsy case of AA systemic amyloidosis associated with IRE This is the third report of AA amyloidosis with IRF and, to our knowledge, the first to show gastrointestinal amyloidosis on autopsy. All patients were women, and 2 of the 3 showed resistance to steroid therapy. These findings may prove helpful in identifying prognostic and risk factors as well as providing insight into the pathogenesis of AA amyloidosis associated with IRE

REPORT OF A CASE

A 67-year-old woman with a urinary tract infection presented to the urology department with a retroperitoneal mass lesion identified at another hospital. The patient had a history of diabetes, but family anamnesis was unremarkable. The mass was observed around the aorta and inferior vena cava in the abdomen on computed tomography. Drip infusion pyelography indicated no abnormalities other than mild hydronephrosis in the right kidney. The biopsy specimen showed marked infiltration by inflammatory cells with several fibrotic areas (Figure 1, A). Most inflammatory cells were plasma cells, and fibrotic areas were composed of small collagen fibers with fibroblasts (Figure 1, B). Immunohistochemical staining showed that most inflammatory cells were positive for CD79a (Figure 1, C), confirming the presence of B cells. Although CD3^sup +^ T cells and CD68^sup +^ histiocytes were also found, these cells represented minor populations (

Four years later, the patient complained of fatigue, edema, severe diarrhea, and fecal incontinence. The extent of the IRF was almost identical to that found 4 years earlier on computed tomography. To determine the cause of enteropathy, biopsies of the gastrointestinal tract were performed. Specimens showed massive deposition of homogeneous eosinophilic protein in the colonic and gastric mucosa. The protein stained positive for Congo red, identifying it as amyloid. On the basis of these findings, malabsorption syndrome from gastrointestinal amyloidosis was diagnosed. Despite several nosotropic treatments, the patient died of heart failure 3 months later. To determine the relationship between the amyloidosis and IRF, an autopsy was performed with the consent of the family.

MATERIALS AND METHODS

Histology and Immunohistochemistry

Samples from the biopsy and autopsy were fixed in 10% formaldehyde solution and embedded in paraffin. Four-micrometer-- thick serial tissue sections were prepared and stained with hematoxylin-eosin. Immunohistochemical examinations were also performed with an Envision kit (Dako Corporation, Kyoto, Japan). Primary antibodies (Dako) used in this study included antiCD3 (prediluted), anti-CD68 (prediluted), anti-CD79a (prediluted), anti-AA component (1:100), anti-kappa light chains (1:10000), anti-gamma light chains (1:20000), and anti-beta2 microglobulin (1:300).

Electron Microscopy

Deparaffinized samples for examination by electron microscopy were fixed in 2% osmium tetraoxide, dehydrated, and embedded in Epon. Ultrathin sections were stained with uranil acetate and lead citrate prior to observation with an H-7000 electron microscope (Hitachi, Tokyo, Japan).

PATHOLOGIC FINDINGS

Gross pathology showed soft and grayish IRE Although fibrosis had advanced to some extent, the infiltration of numerous plasma cells was still evident. Furthermore, the deposition of amyloid proteins was observed in the vascular walls of various organs, including the heart, kidney, adrenal gland, liver, pancreas, stomach, duodenum, small and large intestines, and IRE The mucosa of the gastrointestinal tract, particularly the stomach and duodenum, showed the highest levels of amyloid deposition (Figure 2, A). These were strongly positive for Congo red and exhibited apple green birefringence when polarized (Figure 2, B and C). In election microscopic analysis, the protein was visible as a collection of 10-nm-wide, straight unbranched filaments randomly oriented as a meshwork (Figure 3), thus confirming that it was an amyloid protein. Finally, we examined the type of amyloid protein. Congo red staining yielded negative results with potassium permanganate. In addition, the amyloid material stained positive for AA component (Figure 2, D) but not for kappa light chains, gamma light chains, or beta^sub 2^-microglobulin. These results strongly indicate that the amyloidosis was AA type and that it was secondarily induced by IRE

COMMENT

We have presented an autopsy case involving gastrointestinal AA amyloidosis associated with IRF in a 67-year-- old woman. To our knowledge, only 2 cases of IRF with AA amyloidosis have previously been reported, and this is the first case in which an autopsy was performed (Table).5,6 Although the etiology of IRF is poorly understood, it is considered a chronic inflammatory disorder.2 Because AA amyloidosis is generally induced by chronic inflammatory diseases, IRF may induce AA amyloidosis.

All 3 described patients were women. Although this population is extremely low, the finding offers a potentially interesting contrast to the male predominance normally observed in IRE.1 The reasons for this possible gender association are unknown, and further investigation is needed to determine whether conditions such as hormonal or autoimmune factors play a role in the induction of AA amyloidosis with IRE

In addition, 2 of the 3 patients showed resistance to steroid therapy for IRE Information regarding the response to therapy was unavailable for the remaining patient. Although the exact mechanism is unknown, it should be noted that this resistance might impair the prevention or treatment of AA amyloidosis, since the active inflammation itself induces AA amyloidosis, and the primary treatment for AA amyloidosis is to reduce the inflammatory activity.3,7 In the present case, fibrosis had not advanced substantially for 4 years, indicating that inflammatory activity had continued. Because steroid therapy is effective for IRF unless fibrosis is advanced,1 there are 2 possible mechanisms for the resistance seen in the present case. One possibility is an intrinsic low response to the steroid in plasma cells, perhaps caused by defects in the signaling pathway, and the other possibility is very high inflammatory potential overcoming the steroid effect.

With regard to the time from the diagnosis of IRF to the induction of AA amyloidosis, the patient of the present study showed a relatively short course of 4 years; however, the median time for the progression of other inflammatory diseases to AA amyloidosis is 12 years.8 Furthermore, this patient died only 3 months after being diagnosed with amyloidosis. These observations indicate that the patient of the present study showed very strong progressive activity, possibly attributable in part to the steroid resistance described above.

Whereas nephrotic syndrome due to amyloid deposition in the glomeruli represented the main disease in the 2 cases described previously, malabsorption syndrome was the most apparent in the present case, with extensive deposition of amyloid in the gastrointestinal mucosa. Although amyloid was deposited in the small and medium arteries of the kidney in the present case as a part of systemic amyloidosis, the glomeruli were basically intact, and a low level of proteinuria was shown. As a result, this is, to our knowledge, the first case in the literature to show gastrointestinal AA amyloidosis as the dominant finding.

Given these findings, it is possible that IRF is an etiologic factor associated with AA amyloidosis. Although only 3 cases have been reported, 2 of the 3 patients of these cases were women with IRF who showed resistance to steroid therapy prior to the induction of AA amyloidosis. These findings may be helpful in determining the prognosis and risk factors as well as the pathogenesis of AA amyloidosis associated with IRF.

The authors gratefully acknowledge the invaluable technical assistance of Mr M. Ogawa, Mr T Matsumoto, Mrs H. Ogaki, and Mr K. Nagaoka.

References

1. Lepor H, Walsh PC. Idiopathic retroperitoneal fibrosis. J Urol. 1979;122:1-6.

2. Osborne BM, Butler J), Bloustein P, et al. Idiopathic retroperitoneal fibrosis (Sclerosing retroperitonitis). Hum Pathol. 1987;18:735-739.

3. Sipe JD, Cohen AS. Amyloidosis. In: Fauci AS, Braunwald E, Isselbacher KJ, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGrawHill; 1998:1856-1860.

4. Kisilevsky R, Lyon AW, Young ID. A critical analysis of postulated pathogenic mechanisms in amyloidogenesis. Crit Rev Clin Lab Sci. 1992;29:59-82.

5. Littman E. Renal amyloidosis with nephrotic syndrome associated with retroperitoneal fibrosis. Ann Intern Med. 1971;74:240-241.

6. Bayes B, Garcia FF. The nephrotic syndrome, AA amyloidosis and a retroperitoneal tumor mass in a 20-year-old female patient. Med Clin (Barc). 1998; 111:751-757.

7. Steel DM, Whitehead AS. The major acute phase reactants: C-reactive proteins, serum amyloid P component and serum amyloid A protein. Immunol Today. 1994;15:81-88.

8. Gillmore JD, Lovat LB, Persey MR, et al. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet. 2001;358:24-29.

Naoki Hosaka, MD, PhD; Masaaki Ito, MD; Yoji Taki, MD; Hiroshi Iwai, MD, PhD; Junko Toki, PhD; Susumu Ikehara, MD, PhD

Accepted for publication January 24, 2003.

From the Departments of Clinical Pathology (Dr Hosaka) and Urology (Drs Ito and Taki), Toyooka Hospital, Toyooka City, Hyogo, Japan; the Department of Otolaryngology (Dr Iwai) and the First Department of Pathology (Drs Toki and Ikehara), Kansai Medical University, Moriguchi City, Osaka, Japan.

Reprints: Naoki Hosaka, MD, Department of Clinical Pathology, Toyooka Hospital, 6-35 Tachino-cho, Toyooka City, Hyogo 668-8501, Japan (e-mail: hosakan@mxa.nkansai.ne.jp).

Copyright College of American Pathologists Jun 2003
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